Synthesis of Cyclopenta[b]piperazinones via an Azaoxyallyl Cation

Letter Cite This: Org. Lett. 2018, 20, 7405−7409

pubs.acs.org/OrgLett

Synthesis of Cyclopenta[b]piperazinones via an Azaoxyallyl Cation Boubacar Baldé,§ Guillaume Force,§ Lucile Marin,§ Régis Guillot,§ Emmanuelle Schulz,§ Vincent Gandon,*,§,† and David Lebœuf*,§ §

Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS UMR 8182, Université Paris-Sud, Université Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France † Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Université Paris-Saclay, route de Saclay, 91128 Palaiseau cedex, France

Org. Lett. 2018.20:7405-7409. Downloaded from pubs.acs.org by UNIV OF WINNIPEG on 12/19/18. For personal use only.

S Supporting Information *

ABSTRACT: A new and efficient reaction sequence between 2-furylcarbinols, anilines, and α-haloamides has been developed to afford highly functionalized cyclopenta[b]piperazinones. This transformation was accomplished through an aza-Piancatelli cyclization/azaoxyallyl cation trapping with a complete control of the diastereoselectivity.

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new route for the straightforward construction of cyclopenta[b]piperazinone derivatives. In recent years, our group has been engaged in the development of the aza-Piancatelli cyclization and its utilization to provide a large array of nitrogen-containing molecules, such as 4-aminocyclopentenones, cyclopenta[b]pyrroles and related compounds.6,7 From there, we envisioned that combining this reaction with the use of azaoxyallyl cations,8 which are putative 1,3-dipoles, would allow us to rapidly forge cyclopenta[b]piperazinones in a one-pot fashion (Scheme 1). Combining the aza-Piancatelli reaction with another transformation to access complex molecules is not unprecedented; however, in our case, it would be the first time

iperazinones represent an important class of nitrogen heterocycles, whose scaffold can be encountered in a large variety of natural products and bioactive molecules (Figure 1).1 As a result, developing original synthetic methods to

Scheme 1. Our Strategic Approach towards Cyclopenta[b]piperazinones

Figure 1. Piperazinones and related compounds occurring in bioactive molecules.

access these synthons has been a steady endeavor for organic chemists in the past decades, especially since they can also be used as direct precursors to piperazines, which are key players in drug discovery.2 However, among piperazinone derivatives, the synthesis of cyclopenta[b]piperazinones remains clearly underdeveloped, even if this scaffold is featured in agelastatin A, which possesses a broad range of potent biological properties, notably antitumor activities, and, thus, has prompted widespread efforts toward its total synthesis.3,4 Moreover, this motif can be found in compound 1, which is a precursor for antidepressants.5 Surprisingly, to the best of our knowledge, no general method for the synthesis of such skeletons has been reported to date. In this context, our aim was to play our part in addressing this anomaly and open up a © 2018 American Chemical Society

Received: September 28, 2018 Published: November 27, 2018 7405

DOI: 10.1021/acs.orglett.8b03103 Org. Lett. 2018, 20, 7405−7409

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Organic Letters

1, entries 1−6). The utilization of Na2CO3 and, to a lesser extent, K2CO3 afforded the best results, delivering compound 5a in yields of 82% and 77%, respectively, in 2 h at room temperature (Table 1, entries 1 and 2). During the course of the reaction, we observed the formation of 6 (∼30%−40% yield), which arose from the elimination of hydrogen bromide. Since this compound is unreactive under the reaction conditions, the transformation required an excess of 4a (2 equiv) to reach more satisfying yields. The reaction sequence could also be performed in trifluoroethanol (TFE), albeit in a lower yield (62%; see Table 1, entry 7). Of note, the reaction could be conducted on a larger scale, starting with 3 mmol of aniline, albeit proceeding at a slower rate (Table 1, entry 8). With the optimized conditions in hand, we evaluated the scope of the reaction with a variety of anilines, 2-furylcarbinols, and α-haloamides (Scheme 2). Generally, the desired products were obtained in good to excellent yields (up to 95%). Regarding the reactivity of the aniline partner with 2furylcarbinol 2a and α-haloamide 4a, the reaction sequence proved to be compatible with the presence of electrondonating (5b) and electron-withdrawing groups (5c−5e), a simple aniline (5f), and even sterically hindered anilines (5g). However, in the latter case, the temperature of the reaction had to be increased at 40 °C during the second step of the process to allow the reaction. Of note, X-ray crystallography of compound 5c unambiguously confirmed the structure proposed for cyclopenta[b]piperazinones (Figure 2). Then, we examined the influence of the substitution at the carbinol and found that the presence of various functional groups, such as alkyl, heteroaryl, alkenyl, and sterically hindered aryl (5h− 5n), did not affect the reactivity. In the case of heteroaryl substituents, the acidity of HFIP was sufficient to trigger the aza-Piancatelli without requiring the calcium salt (5k and 5l). In addition, the reaction was not limited to the use of secondary 2-furylcarbinols but could also be extended to tertiary 2-furylcarbinols (5o). Finally, we explored the reactivity of α-haloamides. Methyl, phenyl, and tert-butyl groups, in place of the benzyl group, were also suitable substituents to furnish the corresponding cyclopenta[b]piperazinones in excellent yields (5q-5r). Moreover, this type of reaction sequence could give access to spirocyclic compounds such as 5p (86%). In the case of a secondary bromide, the reaction afforded the desired product in a good yield and diastereoselectivity (5t) (see the Supporting Information (SI) for NOESY analysis). On the other hand, it was necessary to switch bases from Na2CO3 (33%) to K2CO3 (53%). To our delight, the introduction of a phenyl group at C3 of the furan ring did not hamper the reactivity to access product 5u in 78% yield with remarkable control of the diastereoselectivity on four contiguous stereocenters, which was corroborated by NOESY analysis (see the SI for details). In addition, the diastereoselective reduction of the ketone was achieved to give the corresponding aminocyclopentitol derivative 7, thanks to the steric hindrance exhibited by both phenyl groups in the α-position of the carbonyl (Scheme 3). Based on the result obtained with substrate 2j, we turned our attention to the precursor 2k, which incorporates an azido moiety on the furan ring. Gratifyingly, the reaction sequence enabled the formation of the corresponding product 5v as a single diastereoisomer in 81% yield (eq 1). The relative configuration of the functional groups was ascertained by NOESY analysis (see the SI for details). Interestingly, the azido

that it could be achieved without requiring the preinstallation of a second nucleophile or electrophile onto the 2-furylcarbinol and/or aniline moieties.7 Since the seminal work of Jeffrey’s group,9 the use of azaoxyallyl cation intermediates has been extensively studied in synthesis to furnish a large variety of nitrogen-containing heterocycles.8,10 Azaoxyallyl cations can be easily generated in situ from α-haloamides and common bases. In addition, a close look at the literature showed us that fluorinated alcohols, notably hexafluoroisopropanol (HFIP), are the solvents of choice for reactions involving azaoxyallyl cations, which might be explained by the strong hydrogen-bonding ability of HFIP combined with its excellent solvation properties regarding the stabilization of cationic species.11 In addition, the same applies to the aza-Piancatelli cyclization,6b reinforcing the feasibility of our strategy for the implementation of a one-pot sequence. Another potential interesting feature is that, during this process, two nitrogen functionalities in a syn relationship could be installed, providing an entry point to other molecules of interest such as piperazirum12 or pactamycin,13 following a ring-opening process. Herein, we describe our findings on this reaction sequence, which proves to be compatible with a broad range of 2-furylcarbinols, anilines, and α-haloamides to give the desired cyclopenta[b]piperazinones in excellent yields. DFT computations were also performed to shed light on the mechanism of the transformation. Initially, we investigated the reactivity of 2-furylcarbinol 2a, p-anisidine 3a, and α-haloamide 4a, in a one-pot sequence, to provide the desired cyclopenta[b]piperazinone 5a (Table 1). Table 1. Reaction Sequence Optimizations To Access Cyclopenta[b]piperazinone 5a

entry

basea

solvent

t (h)

yield 5a (%)

1 2 3 4 5 6 7 8b

Na2CO3 K2CO3 Cs2CO3 Et3N DBU DMAP Na2CO3 Na2CO3

HFIP HFIP HFIP HFIP HFIP HFIP TFE HFIP

2 2 2 3 6 6 2 4

82 77 70 73 50 47 62 77

a

DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DMAP = 4-dimethylaminopyridine. bStarting from 3 mmol of aniline 3a.

Using our standard conditions for the aza-Piancatelli cyclization (Ca(NTf2)2/nBu4NPF6 (5 mol %) in HFIP (0.3M)), we accomplished the first step to generate the corresponding 4-aminocyclopentenone (see Scheme 1). The reaction had to be performed with an excess of 2-furylcarbinol (1.5 equiv) to ensure the complete consumption of the aniline in 2 h and, thus, prevent any side reaction with the αhaloamide during the second step. Then, α-haloamide 4a was added to the reaction mixture along with various bases (Table 7406


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Organic Letters Scheme 2. Substrate Scope for the Preparation of Cyclopenta[b]piperazinones

Figure 2. ORTEP view of compound 5c (thermal ellipsoids at 50% probability level).

Scheme 3. Preparation of Aminocyclopentitol 7

present in pactamycin (see Figure 1), not to mention the oxygen and methyl groups as well. Regarding these derivatives, we wanted to demonstrate that we could selectively cleave the functional groups on the nitrogen, depending on the reaction conditions employed for compound 5a. Thus, in the presence of Mo(CO)6, the benzyloxy group could be selectively removed in 74% yield (eq 2). On the other hand, the cleavage of the p-methoxyphenyl

[a] Ca(NTf2)2/nBu4NPF6 were not required for step (1). Mes = 2,4,6trimethylphenyl.

group proved to be more problematic. If the deprotection in the presence of cerium ammonium nitrate (CAN) occurred without any problem, which was confirmed by mass spectrometry, the resulting product, unfortunately, rapidly decomposed.

functionality remained intact during this process, while it is known to react with azaoxyallyl cations.10c Thus, via this method, it is possible to install all the nitrogen functionalities 7407


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the reactive form and the azaoxyallyl cation appear to be an oxirane-2-imine in this reaction, and a stepwise process seems to be operative.17 In summary, we have devised an elegant and novel intermolecular strategy to give rise to cyclopenta[b]piperazinones in excellent yields with complete control of the diasteroselectivity, which can go up to four contiguous stereocenters. Moreover, for the first time, we succeeded in gaining a better insight into the mechanistic behavior of azaoxyallyl cations by means of DFT computations. Regarding the potential of this reaction sequence, complementary studies are underway to trigger the ring-opening of both cyclopentane and piperazinone units in order to enhance the synthetic utility of this transformation and use it for the synthesis of bioactive molecules.

Finally, the mechanism of the title reaction was studied by means of DFT computations to understand the reactive form of the azaoxyallyl cation and the steps involved (Scheme 4). In Scheme 4. Computed Intermediates and Transition States (ΔG298, in kcal/mol)

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b03103. Experimental procedures, characterization data, 1H and 13 C NMR spectra for all new compounds, coordinates and energy of the computed species (PDF) particular, we wanted to know whether, in our case, the azaoxyallyl cation could react as a 1,3-dipole and, therefore, promote a concerted reaction, as it is often mentioned in the literature.8 The calculations were performed using the Gaussian 09 software package and the ωB97XD functional (see the SI for details). The 6-31G** basis set was used for optimizing the minima and transition states. Energies were then refined through single-point calculations with the 6311+G** basis set. Solvent correction for HFIP was obtained with the SMD model as described previously.14 The values discussed are ΔG298 (in kcal/mol). It was not possible to compute an open form of the azaoxyallyl cation that would correspond to B′′ in Scheme 3. This type of intermediate has been reported as minimum when the B3LYP functional was used,9,15 but we could not have it converge with the ωB97XD one. Instead, this compound converged either as aziridinone B′ or as oxirane-2-imine B, the former being more stable by 3.3 kcal/mol. However, no reaction between B′ and the 4aminocyclopent-2-enone A could be modeled. On the other hand, studying the attack of the amide moiety of A to the quaternary carbon of oxirane-2-imine B allowed to locate the N−C bond forming transition state TS[AB]C, lying only 9.0 kcal/mol above the [A·B] adduct.16 It does not lead directly to a bicyclic product, but to ammonium C, which is obtained in an exergonic fashion (−4.3 kcal/mol). The subsequent Michael addition step could not be modeled from C, nor from its more-stable isomer D, which was obtained after N to O proton transfer. On the other hand, the Michael addition could be computed after deprotonation of C or D to give C′. It requires 10.7 kcal/mol of free energy of activation to reach TSC′E′ from C′, located at −38.3 kcal/mol on this new deprotonated potential energy surface. The final compound E′ is more stable than the [A′·B] adduct by as much as 48.0 kcal/ mol. Of note, the reaction of A′, which corresponds to the deprotonated form of A, with B, could also be computed, but the direct deprotonation of A by the base seems less likely than that of C or D. Thus, we suppose that the followed pathway corresponds to A+B, C, possibly D, C′, and finally E′. Thus,

Accession Codes

CCDC 1870148 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (V. Gandon). *E-mail: [email protected] (D. Lebœuf). ORCID

Emmanuelle Schulz: 0000-0002-0844-8825 Vincent Gandon: 0000-0003-1108-9410 David Lebœuf: 0000-0001-5720-7609 Author Contributions

The manuscript was written through the contributions of all authors. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully thank the ANR (No. ANR-16-CE07-0022, to G.F.), the CNRS, the Ministère de l’Enseignement Supérieur et de la Recherche, the Université Paris-Sud and the Institut Universitaire de France (IUF) for their support of this work.

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REFERENCES

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Synthesis of Cyclopenta[b]piperazinones via an Azaoxyallyl Cation

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